Importance of Bone Health Agents in mCRPC Management

Jorge A. Garcia, MD, FACP: I want to a talk briefly about the importance of bone health agents. When I think of bone health agents, I remind the group of 2 important things. Prostate cancer loves to spread to the bones. It’s a bone-tropic disease. The treatments we use lead to bone loss. Remember, if you put me on androgen suppression therapy at age 51 for a year, I probably will have a significant increase in bone loss in bone mineral density. It’s around 5% to 7% per year. So this is real. The fact is, most of our men with prostate cancer are older, so men start losing bone density when they turn 32, 35, maybe 40. What happens as we get older is we start developing osteopenia, osteoporosis. In addition to that, we have a disease that loves to go to the bone. We have agents and treatments that are effective but can cause further bone loss, so that’s a complication. So the 3 things together are leading to significant issues.

When you think of bone health and the importance of bone health, I think of 3 buckets. There are patients who need to be on androgen deprivation therapy [ADT] for the long term who do not have metastatic disease. Specifically, I would argue not metastatic castration-resistant prostate cancer [CRPC]. For metastatic castration-sensitive prostate cancer or biochemical recurrence and men who start androgen deprivation therapy, the goal for those patients would be to minimize their risk of bone loss, to minimize their risk of developing osteopenia, osteoporosis, and pathological fractures related not to cancer but to the effect of low testosterone levels.

The second bucket is, can we use bone health agents or bone-targeted agents in people with M0 CRPC? That means men who don’t have metastatic disease objectively visualized in imaging technology, whatever imaging technology one may use. Can we use those agents as an anticancer effect to delay the presence of bone metastases and maybe even improve outcome? The third bucket is perhaps where we have the bulk of the data, which is in men with metastatic castration-resistant prostate cancer with bone metastases.

Let me address the frontline bucket. If you look at the importance of ADT in the management of men with advanced prostate cancer, again we talk about bone loss. The goal would be for us to lead to bone prevention. When you do that, the existing agents we have used are oral bisphosphonates, IV [intravenous] bisphosphonates, I think the phase 3 data we have would certainly support the use of zoledronic acid, perhaps the RANK ligand inhibitor, denosumab in the context of the best data for those patients. The important part is, however you decide which agent is feeding your practice and your patient, it is important to recognize that there are agents that can be given to patients to minimize bone loss, not to delay prostate cancer, not with the intent of decreasing skeletal-related events in that context. This is because those patients don’t have symptomatic progression or radiographic progression.

The second bucket is can we use bisphosphonates and/or RANK ligand inhibitors for patients with M0 CRPC. That is actually the genesis of a couple of trials. This is the trial that actually Matthew Smith published many years ago in JCO [Journal of Clinical Oncology] that has been used as the key PSA [prostate-specific antigen] doubling time feature to develop agents in the M0 CRPC. That data with zoledronic acid was aborted because the primary end point couldn’t be met at the time. Yet some people still believe in the use of zoledronic acid in that context.

There was a trial looking at denosumab against placebo for people with M0 CRPC with the goal of delaying rPFS [radiographic progression-free survival] and survival improvement. I can tell you that using denosumab did delay rPFS by 3.4 months. However, there was no survival improvement, and to my understanding maybe that was the reason why that agent was not FDA labeled in that space. However, if you have patients with M1 or metastatic castration-resistant prostate cancer with bone metastases, there are plenty of data to use bisphosphonates and RANK ligand inhibitors to decrease the likelihood of one developing a skeletal-related event—again defined by pathological fractures, spinal cord compression, the need for radiation therapy, and the need for orthopedic surgery.

So we have plenty of data. We have a trial that was placebo versus a low dose of zoledronic acid of a higher dose, and that data demonstrated that zoledronic acid, given to patients on a monthly basis, did delay, in a significant manner, skeletal-related events and for many years that’s what we used to do. Then we used denosumab, and denosumab was actually compared with zoledronic acid in a unique trial fashion. This was a phase 3 trial that was already published looking at a noninferiority design to demonstrate that denosumab, given to the same patient population, was not inferior compared with zoledronic acid for SRE [skeletal-related event] prevention.

We think the same trial was statistically built as a superiority design, which means that if the drug met the noninferiority boundary, they will proceed to test for superiority. Denosumab was not only noninferior but also met the superiority definition. That data are what I use, what I counsel patients with to tell them that denosumab becomes the standard of care for bone health agent in the castration metastatic setting. The goal again is different and is to delay skeletal-related events.

With the zoledronic acid, based on payers, clinical practice models, care pathways, or denosumab, the important part is we have compelling data that bone health agent is of paramount importance to our patients. Not only for bone loss prevention—minimizing the risk of osteopenia, osteoporosis—but also for us to minimize the risk of someone developing skeletal-related events. This is something we see quite a bit when we use a lot of the old ADT, the new-generation oral agents, in fact all these class of radiopharmaceuticals as well. We don’t know if 1 leads to another. But clearly, because of bone-tropic issues with prostate cancer, most men, if not all men, with metastatic castration-resistant prostate cancer with bone metastases should be on a bone-health-protecting agent.

Oftentimes the biggest question is, how do you do it? If I had a patient getting systemic chemotherapy every 3 weeks, I would probably not put the patient on zoledronic acid or denosumab every 3 weeks. We’d probably do it every other time, even though that would go against the published data. The Europeans have data using zoledronic acid every 3 months for breast cancer, so I think most people in practice will keep the patient on a bone health agent.

For the decision on how often you do it, you can follow specifics of the trial and do it like that—straight perspective, validated level 1 evidence—or you can adapt your practice. The important part is just to make sure and to follow the patient for adverse effects because there are unique adverse effects to bone health agents. With zoledronic acid, you can have a little bit of flu-like symptoms, issues with renal dysfunction, and also the concerns for osteonecrosis of the jaw, or ONJ.

With denosumab, you don’t have the issues of renal dysfunction. You don’t have issues with flu-like symptoms, but you have issues with ONJ as well and hypocalcemia, which are important for us to pay attention to. It’s also very important for you to remind patients in any given setting or disease state in prostate cancer of the importance of smoking cessation; active and vigorous weight-bearing exercise, because that allows you to build bone mass; and healthy diets.

Consumption of caffeine and carbonated substances are important to pay attention to and also vitamin D and calcium supplementation for a significant number of these patients. That is usually what I talk to my patients about from the conception of their disease. Throughout their natural history, I start adapting based on their needs and what their disease states are.

Transcript edited for clarity.

Case:A 69-Year-Old Man with Advanced Castrate Resistant Prostate Cancer

Initial presentation

• A 69-year-old man presented with intermittent back discomfort and loss of appetite
• PMH: hyperlipidemia controlled on a statin, no known family history of cancer
• PE: DRE revealed asymmetric, boggy prostate; otherwise unremarkable

Clinical Workup

• Biopsy with TRUS showed adenocarcinoma of prostate
  • Stage T2N0M0
  • Grade group 4
• Germline genetic testing: MLH1, MSH2, MSH6, PMS2, BRCA1/2, ATM, PALB2 and CHEK2
• Chest/abdominal/pelvic CT scan showed no evidence distant metastases or lymph node involvement
• Bone scan was negative
• PSA 24.9 ng/mL

Treatment and Follow-Up

• EBRT + ADT was started
• Follow up at 6 months, PSA 11.2 ng/mL
• At 12 months PSA 18.6 ng/mL
  • Patient reported increasing back discomfort and difficulty walking
  • Bone scan at that time showed multiple vertebral lesions at L3/L4
• Treatment with radium-223 dichloride was initiate
  • 6 infusions were completed, treatment was well tolerated